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8CHEMISTRY
STUDYING AND CREATION OF NEW ANTAGONISTS OF APOPTOSIS AMONG AMIDOETHERS AND DIAMIDOTHIOETHERS OF PHOSPHORIC ACID
Aimakov A.,
Sh. Ualikhanov Kokshetau State University, Kokshetau, Kazakhstan, Doctor of Chemical Sciences
Kirillov V.,
Kazakhstan Research Institute of Forestry, Head Department of Biotechnology,
Schuchinsk, Kazakhstan, PhD Belgara B.,
Faculty of Natural Sciences, Eurasian National University named after L. N. Gumiliev,
Nur-Sultan, Kazakhstan, MSc Nurmukhanbetova N.
Sh. Ualikhanov Kokshetau State University, Kokshetau, Kazakhstan, Candidate of Chemical Sciences Abstract:
Synthesis and comprehensive research of features of organophosphorus compounds containing P-N bonds in their structures are actual for the purpose of obtaining new biologically active substances and their application in medicine, veterinary and agricultural sector.
We carried out the interaction of monoethnolamide etheramides with 0,0' -dyalkylthiophosphites in an environment of carbon tetrachloride in a presence of triethylamine, and obtained corresponding products of ToddAtherton reactions with the yield of 55-79%.
R—O .S
V
R-O H
X'
N S
R—O NH
\ A
O nCH2, Et,N, CCl4
- Et,NHCl, - CHCl3
R-O /S
R-O^ NH O \
X
NS
/P N ,
R'—O NH O __
R = Me (1), Et (2), n-Pr (3), i-Pr (4), n-Bu (5)
X = O, R = n-Pr (6), n-Bu (7)
X = CH2, R' = n-Pr (8), n-Bu (9)
The structures of new synthesized compounds were investigated by quantum-chemical methods. Initial structures were obtained by molecular mechanics methods, using Instant JChem v.5.3.1. The obtained structures were optimized with help of semi-empirical quantum chemistry (Hamiltonian RCM, HyperChem 8.0 and MOPAC 2009 softwares). The geometrical, electron and energetic characteristics of these compounds were calculated.
Some physical and chemical features (molar refraction, density, refractive index, boiling point, logP, pKa, etc.) of these compounds were calculated using ACD/Labs v.12.0 and InstantJChem v.5.3.1 softwares. The computer software for the prediction of biological activity spectra PASS revealed that 00-dialkyl-[N-2(vi-nyloxy)ethylamido]thiophosphates can be an antagonists of apoptosis. Apoptosis is such type of cell death at which the cell actively participates in process of its death, which is a self-destruction of the cell. Antagonist is a substance that blocks the receptor and thereby weakens and completely prevents the action of another substance. The probability of this activity is high and amounts to 68.1-73.6% (the highest probability is at compound 8). it is advisable to conduct experimental studies to confirm the forecast.
Keywords: phosphorus, amidoethers, heteroatoms, apoptosis antagonists, hydrothiophosphates, Schiff bases.
1. Introduction tiophosphorus organic compounds that are promising
Hydrophosphoryl and hydrotiophosphoryl com- for further research in order to find the important bio-pounds (HPS and HTPS) and their derivatives comprise logically active compounds.
a very interesting area of chemistry of phosphorus and
HN
Many synthesized compounds based on HPS and HTPS were tested for biological activity, and in most cases they showed aphicidal, fungicidal, anthelmintic activity and antitumor effect and relatively low toxicity to warm-blooded animals.
The identified primary law of interrelation of chemical constitution and biological effect of medicines allows conducting directional synthesis of new compounds soon.
Investigations in this area (the chemistry of organic phosphorus compounds) showed that new high efficient, low-toxiferous biomedical medicines, as well as therapeutic and prophylactic substances can be found among these compounds.
The development of this field of organophospho-rus compounds (OPC) is very interesting and perspective. HPS and HTPS are highly reactive, and it's possible to pass further on their basis to other POC classes, containing P-C, P-N and P-C-N bonds. In order to carry out the synthesis of substances or various structures, it is first necessary to develop methods of obtaining available starting materials.
There are various methods for synthesis of OPC, however, compounds containing functional groups -P(O)H or hydrophosphoryl and -P(S)H or hydrothio-phosphoryl are of particular importance as the phos-
phorylating reagents. Results of researches on chemistry of HPS and HTPS are published in several tens of thousands articles and patents, and the most important are generalized in monographs and reviews [1-4].
It is known that HPS and HTPS and their derivatives possess a wide range of physiological activity. They are widely used as plant protection products from crop pests, herbicides, plant growth regulators and medicines.
Therefore, the study of properties of new functionally substituted derivatives of certain ethers of HPS and HTPS and new biologically active substances is of interest.
The research of OPC reactions, which have unique properties in some cases, expands and deepens ideas not only of their chemical behaviour and mechanisms of their transformations, but also allows finding out features of chemical properties of organic compounds with which they react, thereby enriches both organophos-phorus chemistry, and bioorganic chemistry in particular.
New amidoethers and diamidoethers of thiophos-phoric acid with various radicals were obtained in the present work using the reaction of Todd-Atherton. Schemes of this reaction mechanism are presented below:
O
^ , b O
(RO)P + CC14 + HOR1 (RO)2P-OR1 + CHC13 (1)
H
In this case, first chlorophosphate is formed, which further phosphorylates nucleophile: O O
/ B II
(RO)P B (ROP-O -(ROP-C1 + -CQ3 (2)
H
O
//
(ROP +-CH3 —a- (TQPO +CHl (3)
H
In this scheme, in the presence of light, chlorine turns these compounds into chlorphosphates. Joining of dialkylphosphites to alkenes with formation of secondary phosphonates also causes concern. Reaction is carried out in the presence of the organic peroxides that initiate the appearance of phosphorus-containing radicals:
R1O-OR ^ R1O* (4)
(RO2)P + OR1 —^ (RO2)P- (5)
H
(R°R +CH=CHR-^ (R°P— CH-CHR-s-
(6)
(R°p°H (RO^P. CHCt^-Ff +(RQ)P.
Finally, dialkylphosphites show alkylating action. Herewith they become salts of monoalkylphosphites, for example:
O °
S II
(R°^P + —s- R° - P - O- R3N+ R1 (7)
H H
The interest in research of organophosphorus compounds chemistry and in investigating of derivatives of ethers of phosphorus acids and thioacids was aroused not only by the development of theoretical concepts in organic and organoelemental chemistry on their basis. Close attention to these derivatives is considerably caused by the broad possibilities of synthesis on their basis of a various practically valuable biologically active compounds, such as insectoacaricide, ne-maticides, herbicides, pharmaceuticals, etc.
Moreover, the study of reactions of organophosphorus compounds (abbreviated as OPC) with specific properties allows to reveal the features of reactivity of reagents, which interact with organophosphorus compounds, apart from expanding representations about reactivity and reaction mechanisms of OPC. It contributes to the study of both the elementoorganic and organic chemistry in general.
Hydrophosphoryl and hydrothiophosphoryl compounds are now widely used for solving many problems of thin organic synthesis. For example, to produce a variety etheramides, aminophosphonates and aminoti-ophosphonates, complex thiosalts and other phosphorus-containing natural salts and their analogues.
It is noteworthy that the hydrophosphoryl and hy-drothiophosphoryl compounds together with other OPCs are frequently used as a phosphorylating reagent. Their advantages are availability, relatively high reactivity and simplicity of conditions of preparative application.
In order to develop the basis of targeted synthesis of new derivatives among hydrophosphoryl and hydrothiophosphoryl compounds, we performed systematic physico-chemical, synthetic and biological studies of the aforementioned class of compounds.
While researching hydrophosphoryl, hydrothiophosphoryl compounds, vinyl ethers of aminoalcohols and alkaloids, we first examined the phosphorylation reaction of a vinyl ether of monoethanolamine and some of a number of heterocyclic amines, such as anabasine, piperidine and morpholine.
As a result of targeted scientific research optimum paths of synthesis of new O-alkylheterocyclic hydrophosphoryl and hydrothiophosphoryl compounds were developed.
On the basis of Todd-Atherton's, Kabachnikov-Fields's [5] and Abramov's [6] classical reactions, we selected optimum conditions for receiving various am-idoethers of phosphoric, thiophosphoric acids, a-ox-ymethylphosphonic, aminophosphonic and aminothio-phosphonic ethers.
Synthetic capabilities of organic chemistry of phosphorus were expanded through the use of new synthetic methods and reagents: asymmetric hydro- and hydrothiophosphoryl compounds, amidoethers of phosphoric and thiophosphoric acids, phosphorylated formals and aminoacetals, aminophosphonic and amino-thiophosphonic ethers.
We widely used a readily available monomer -divinyl oxide of monoethanol amine, and further on its basis the new Schiff bases, having reactive functional groups in their structure, are synthesized. Further various amidoethers of phosphoric and thiophosphoric acids were synthesized by phosphorylation of vinyl ether of monoethanolamine and Schiff bases.
The tasks were successfully solved through the active use of modern physical and chemical methods of research that included IR, PMR, 31P NMR spectroscopy, which ensure the accuracy of the results.
The synthesized compounds can find use as multifunctional initial materials for thin organic synthesis of new asymmetric hydrophosphoryl, hydrothiophos-phoryl compounds and their derivatives. Perspective substances exhibiting pronounced aphicidal, insecti-cidal, anthelmintic, lavocidic, antitumor activity were found among the obtained compounds.
2. Experimental Setup
The previously unknown amidohydrophosphoryl and thiophosphoryl compounds on the basis of hetero-cyclic amines (piperidine, morpholine and anabasine alkaloid) were obtained as the initial substances for the synthesis of ethers of phosphorus acids and thioacids. At the beginning the corresponding dichlorineanhy-drides were obtained from secondary heterocyclic amine and phosphorus trichloride. Without releasing, the corresponding dichlorineanhydrides turn to mono-chlorineanhydrides in the presence of triethylamine. Their soft hydrolysis leads to amidoethers of phosphorus acid. The yield of amidoethers at the rate on heterocyclic amine is from 37 to 49%.
Further, asymmetrical hydrothiophosphoryl compounds with heterocyclic radicals first synthesized using the Lawesson's reagent. The exchange of oxygen for sulphur happens very smoothly when boiling in benzene until complete dissolution of Lawesson's reagent (1.5-3 hours).
Amido(diamido) ethers of phosphorus and thio-phosphorus acids were obtained by the Atherton-Todds reaction from corresponding hydrophosphoryl compounds, secondary bases or vinyl ether of monoeth-anolamine and carbon tetrachloride in the presence of triethylamine. At the beginning, we performed the reaction using simple dialkyl phosphates and thiophos-phates, and then we used asymmetric amidoethers of phosphorous and thiophosphorous acids. The yield of corresponding ethers obtained with the Atherton-Todd's reaction were 70% and higher.
The structures of the asymmetric hydro- and thio-hydrophosphoryl compounds and amidoethers were proven with IR-, NMR 31P spectroscopy methods, the composition were proven with elemental analysis.
When carrying out the experimental works we used the device, which is often applied in thin organic synthesis, consisting of a round-battorn three-necked reactionary glass flask, a mechanical stirrer, a dropping funnel.
For cleaning of the received products the following devices are used: distillation system, columnar chromatograph, fast-efficient gas-liquid chromatograph, refractometer, pyknometer (volume 0,5-1 ml).
3. Experimental Results
It is known that hydrophosphoryl, hydrothiophos-phoryl compounds and their derivatives have a wide range of physiological activity. Some of them are used
as plant protection against agricultural pests, herbicides, plant growth regulators, and pharmaceuticals.
In this regard, a research of properties of new functionally substitution derivates of some ethers of hy-drophosphoryl and hydrothiophosphoryl compounds, and a search of biologically active materials attract interest.
The object of the study is vinyl ethers of amino alcohols, such as monoethanolamine vinyl ether, in order to obtain their phosphorylated derivatives [7-10]. Vinyl ethers of amino alcohols take an important place among the tools which are widely used in thin organic synthesis of vinyl derivatives of heteroatom compounds. The reaction of vinyl ethers of amino alcohols (ethanolamines and propanolamines) with dialkyl halo-gentiophosphite or dialkyl halogenphosphite leads to cyclic derivatives amidophosphate. Phosphorus-containing vinyl ethers can serve as monomers and products for synthesis of biologically active materials. Thus, the vinyl ethers with different functional groups and hetero atoms are of certain theoretical and practical interest. It is known that the addition of alcohols to vinyl alkyl ethers and vinyl ethers of aminoalcohols leads to formation of acetals of various structures. Compounds of this type are easily obtained by phosphorylation of readily available vinyl ethers such as monoethanola-mine vinyl ether and vinyl butyl ether. Phosphorylation of vinyl ethers was carried out with the participation of a-hydroxymethyl phosphonate. Monoethanolamine vinyl ether and monovinyl butyl ether were taken as examples. The mixing of the components at room temperature accompanied by a significant evolution of the reaction mixture heat to 40-420C. Reactions proceed according to the scheme:
RO RO O or
RO\II I
P(O)CHpH+HC=CH-O-R —^ P - CHpCH (8)
rq/ rq/ ch,
p-ch-oh + hn-ch-ch-och=ch2 —»
RO
(9)
RO O O-CH2-CH2-NH2
—^ ^P-CH2-O-CH
RO Ch3
R=Et, Bu, i-Bu; R'=CH3(CH2}3--Hexahydrotriazine and hydrophosphoryl compounds were successfully used for the synthesis of certain derivatives of aminomethylphosphonate, because thus-obtained compounds are of great interest as ligands and physiologically active substances.
Direct action of phosphorus acid ethers to hexahydrotriazine leads to formation of vinyl ethers of ami-nomethylphosphonic acids.
P(O)H + [ \ — P - CHjNH-R (10)
RO RO
I
r'
R=Et, Pr, n-Bu, i-Bu; R'=-CH2CH2-OCH=CH2
Reaction of asymmetric O,O-dialkylphosphorous acids with vinyl ether of monoethanolamine in the condition of Todd-Atherton's reaction were used for synthesis of p-vinyloxyethylamid ethers.
It is known that hydrophosphoryl and hydrothiophosphoryl compounds play a role of the phosphorylating reagent of the second type in Todd-Atherton's reaction. Their activation occurs by reaction with carbon tetrachloride:
RQ
/ ro
p(o)h+ hnchchochch, + (ch)n
oa,
RDV
/ ro
(11)
ponhchchpchch, + (ch^n-hc + chc3
R = Et, R = Pr, R = Pr, R = Bu.
Reaction is carried out at 0-5oC in the environment of carbon tetrachloride in the presence of triethylamine with selection of a product by vacuum distillation. The product yield is 65-71%.
Further, the synthesis of new diamido ethers of phosphoric acid on the basis of monoethanolamine vinyl ether and amido ethers of phosphonic acid was carried out.
CCl^ E^N
h-p=o + hnch,choch=ch2
or
E^N HCl, CHC,
(12)
I
i ro-p=o n" i
nhchch>och=ch
N
I CCL, Et,N
H~P=O + H2NCH2CH2OCH=CH2 1EclNiHct RO CHCl3
(13)
"N"
I
RO—P=O
I
NHCH2CH2OCH=CH2
Numerous published data led to the conclusion of the feasibility of searching in hydrophosphoryl and hydrothiophosphoryl compounds.
It is established that the reaction of O,O-dialkylthiophosphorous acids, including etheramides of thiophos-phonic acid, with vinyl ethers of monoethanolamine under Todd-Atherton's reaction condition goes by the following scheme and leads to the formation of the corresponding O,O-dialkyl-(ft-vinyloxyethyl)-amidotiophosphats:
X
X
RO
RO
PSH n
0
R-Q —PSH
H2NCH2CH2OCH=CH2, Et3N, CCl4 -Et3N HCl, -CHCl3
(14)
RO\// /
PNHCH2CH2OCH=CH2
RO
0
R-Q —P^
NHCH2CH2OCH=CH 2
R = Me, Et, Pr, i-Pr, Bu; R = Pr, Bu; X = O, CH2. Reactions were carried out in benzene at 48-50oC, the yield was 55-79%.
We used anazin and hydrothiophosphoryl compounds to enhance a number of etheramides of acids and phosphorus thioacids. As a result, the corresponding etheramides of phosphorus thioacids with anabazin fragment were obtained [11].
(15)
This method allows to receive derivants of both heterocyclic, and acyclic amidoethers of thiophosphoric acid with high yield.
Reactions of phosphorylation of Schiff bases are widely discussed in scientific and chemical literature in chemistry of ethers of acids and thioacids of phosphorus. Dialkylaminophosphoric and dialkylaminothiophos-phoric ethers were obtained by interaction of Schiff bases with a hydrophosphoryl and hydrothiophosphoryl compounds [12].
RC
^ /-ch=n
/-\
och=ch+ P(X)H-
RO
(16)
/ \
/)—ch—N qch=ch +
— iUx rQ sQR-
R = R' = Me, Et, Pr, i-Pr, Bu, i-Bu, X = O, S.
Amido ethers of phosphonic and thiophosphonic acids, and also amido-(diamido) ethers of thiophosphoric acids with heterocyclic radicals were synthesized as a result of experimental studies.
These compounds may be key intermediates in the organophosphormc synthesis, and of independent interest as potentially biologically active substances, in particular with the insecticide-acaricide and aphicidal activity [1315].
Derivants of ethers of tio- and dithiophosphoric acids are also of the considerable interest, since they lead to the formation of the corresponding ammonium salts by reacting with primary, secondary and tertiary amines.
It is known from literary data, that many tertiary ammonium salts containing higher alkyl radicals and salts of acid ethers of thio- and ditiophosphoric acids in their molecules, have high bactericidal and fungicidal activity.
Interaction of HTPC with anabazina and elemental sulfur is exothermic, resulting in formation of the corresponding thiosalts with yield [16-18].
RO4
RO
XP(S)H +
N
(17)
RO ,S
N
N+ I H H
R = R' = Me, Et, n-Pr, i-Pr, n-Bu. Salts of anabazina O,O- dialkyldithiophosphate were obtained by a different method: by reaction of alkaloid-anabazina with the corresponding O,O-dialkyldithiophosphorous acids.
ro.
ro
,p(s)h +
n
(18)
ro ,s
X
ro xs
n
n+4
i h hh
S
Despite the impressive success achieved in the field of synthesis and studying of properties of hydrophosphoryl and hydrothiophosphoryl compounds, not all problems have been solved. The possibilities of chemical modifications of HPC and HTPC with addition of new more complex heterocyclic radicals, functional groups with certain reactive centers, that are the objects of further chemical reactions, are not exhausted.
It may be assumed that the area of use of HPC and HTPC will be substantially implemented. Besides searching for new highly biologically active substances among derivatives of HPC and HTPC, extremely important types of compounds that are related to their different properties should be expected.
The analyses of the provided materials allow evaluating not only the actual discussed areas of chemistry of HPC and HTPC, but also the areas which have further broad prospects.
4. Conclusions
The corresponding various derivants of ethers of phosphorus acids and thioacids were obtained as a result of experimental works in the field of organic compounds of phosphorus on the basis of hydro- and hydrothiophosphoryl compounds, heterocyclic secondary amines, monoethanolamine vinylether and Schiff base.
The reactivity of multifunctional different het-eroatom-containing hydrophosphoryl and hydrothio-phosphoryl compounds were studied.
The synthesized new asymmetric hydro- and hy-drothiophosphoryl compounds will make it possible to use them for the synthesis of variety amido-, di-amidoethers of phosphoric and thiophosphoric acids.
According to the computer forecast of the PASS program, 1-(1-ethoxyalkyl)piperidines and 4-(1-ethox-yalkyl)morpholines can be effective inhibitors of ATPase with high probability of 65.1-84.7%.
These compounds are optically active. The spatial and electronic structure of the optical isomers of the compounds was investigated for the first time by quantum chemistry methods, and physical and chemical properties were calculated using applications.
In IR spectrums of the received amino- and ami-nothiophosphonew ethers there are following characteristic absorption bands (u, cm-1): 635-660 (P=S), 1035-1060 (P-O-C), 1610-1625 (C=C), 1260-1280 (P=O), 3230-3285 (NH).
The 31P NMR spectrum for the O,O-diethylamino-phosphonate has a singlet in the area of 97.52 ppm, the 31P NMR spectrum of O,O-aminothiophosphonate has a singlet in the area of 93.04 ppm, the 31P NMR spectrum of O,O-diethyl(vinyloxyethyl)aminophosphonate has singlet in the area of 90.11 ppm.
The 31P NMR spectrum for aminothiophosphoryl ethers with cyclic radicals has signals 5p 108,67 ppm, 5p 104,17 ppm, 5p 99,48 ppm, 5p 104,69 ppm.
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